Department of Neurology, Washington University School of Medicine, St Louis, Missouri.
Knight Alzheimer's Disease Research Center, Washington University School of Medicine, St Louis, Missouri.
JAMA Neurol. 2018 May 1;75(5):582-590. doi: 10.1001/jamaneurol.2017.4719.
Circadian rhythm disturbances occur in symptomatic Alzheimer disease (AD) and have been hypothesized to contribute to disease pathogenesis. However, it is unknown whether circadian changes occur during the presymptomatic phase of the disease.
To examine the associations between circadian function, aging, and preclinical AD pathology in cognitively normal adults.
DESIGN, SETTING, AND PARTICIPANTS: This cross-sectional study was conducted using community volunteers from the Knight Alzheimer's Disease Research Center at Washington University in St Louis. Cognitively normal participants (n = 205) underwent 7 to 14 days of actigraphy in their home environment between 2010 and 2012, in addition to clinical assessment, amyloid imaging with Pittsburgh Compound B (PiB), and cerebrospinal fluid biomarker collection. Data collected from 3 years before to 6 months after actigraphy were included. Sixteen participants were excluded owing to incomplete data collection.
Circadian rhythm analysis was performed on actigraphy data using 3 methods: cosinor, nonparametric, and empirical mode decomposition. Preclinical AD was assessed by longitudinal clinical assessment, amyloid imaging with PiB, and cerebrospinal fluid biomarker collection.
Data from 189 participants were included in the analyses. The mean (SD) age was 66.6 (8.3) years, and 121 participants (64%) were women. Older age (β = .247; P = .003) and male sex (β = .170; P = .04), in the absence of amyloid pathology, were associated with a significant increase in intradaily variability, a nonparametric measure of rest-activity rhythm fragmentation, as well as decreased amplitude by several measures. After correction for age and sex, the presence of preclinical amyloid plaque pathology, assessed by positive PiB imaging (mean [SD], 0.804 [0.187] for PiB negative vs 0.875 [0.178] for PiB positive; P = .05) or increasing cerebrospinal fluid phosphorylated-tau to amyloid β 42 ratio (β = .231; P = .008), was associated with increased intradaily variability, indicating rest-activity rhythm fragmentation.
Preclinical AD is associated with rest-activity rhythm fragmentation, independent of age or sex. Aging was also associated with circadian dysfunction independently of preclinical AD pathology, particularly in men. The presence of circadian rhythm abnormalities in the preclinical phase of AD suggests that circadian dysfunction could contribute to early disease pathogenesis or serve as a biomarker of preclinical disease.
在有症状的阿尔茨海默病（AD）中会出现昼夜节律紊乱，并且有人假设这种紊乱会导致疾病的发病机制。然而，目前尚不清楚昼夜节律变化是否发生在疾病的临床前阶段。
研究认知正常成年人的昼夜功能、衰老与临床前 AD 病理学之间的关系。
设计、地点和参与者：这是一项在圣路易斯华盛顿大学的 Knight 阿尔茨海默病研究中心的社区志愿者中进行的横断面研究。认知正常的参与者（n=205）在 2010 年至 2012 年期间在其家庭环境中进行了 7 至 14 天的活动记录仪检测，此外还进行了临床评估、匹兹堡化合物 B（PiB）的淀粉样蛋白成像和脑脊液生物标志物采集。纳入了活动记录仪检测前 3 年到后 6 个月的数据。由于数据收集不完整，有 16 名参与者被排除在外。
使用 3 种方法（正弦、非参数和经验模态分解）对活动记录仪数据进行了昼夜节律分析。通过 PiB 淀粉样蛋白成像和脑脊液生物标志物采集进行纵向临床评估、淀粉样蛋白成像，评估临床前 AD。
189 名参与者的数据被纳入分析。参与者的平均（SD）年龄为 66.6（8.3）岁，121 名参与者（64%）为女性。在没有淀粉样蛋白病理的情况下，年龄较大（β=0.247；P=0.003）和男性（β=0.170；P=0.04）与日内变异性显著增加相关，这是一种非参数的 rest-activity 节律碎片化测量，以及通过几种测量方法降低振幅。在调整年龄和性别后，临床前淀粉样斑块病理学的存在（以阳性 PiB 成像评估[平均值[标准差]，PiB 阴性为 0.804[0.187]，PiB 阳性为 0.875[0.178]；P=0.05）或脑脊液磷酸化 tau 与淀粉样蛋白β42 比值的增加（β=0.231；P=0.008）与日内变异性增加相关，表明 rest-activity 节律碎片化。
临床前 AD 与 rest-activity 节律碎片化有关，与年龄或性别无关。衰老也与昼夜功能障碍有关，而与临床前 AD 病理学无关，尤其是在男性中。AD 临床前阶段昼夜节律异常的存在表明昼夜功能障碍可能导致早期发病机制或作为临床前疾病的生物标志物。
